Pilot Research Project 1: A Phase 1b Trial of Oligomeric Procyanidin Complex in Combination with Metformin for Reduced AGE Levels in Prostate Cancer Patients Receiving Androgen Deprivation Therapy RESEARCH SUMMARY Advanced glycation endproducts (AGEs) are reactive metabolites produced as by-products of sugar metabolism and oxidative stress. An extensive literature links AGEs with the pathophysiology of diabetes mellitus and other chronic diseases. The U54 investigators have identified preferential accumulation of AGEs in prostate cancer (PCa) serum and tumor, compared with normal serum and prostate tissue. Furthermore, among PCa patients, AGE accumulation is higher in blacks with African ancestry (AAs) than in European Americans (EAs). As AGEs appear to promote cancer survival and growth, interventions to limit their accumulation may be viewed as potential cancer therapeutic agents. These agents may be attractive components of multi-faceted treatment regimens for populations with high prevalence of poor diet, low income, obesity, and lack of exercise. These are all lifestyle factors that are known to increase cancer burden, and are often prevalent in AAs. The study investigators propose to conduct a Phase Ib clinical trial of a combination of two potential agents to reduce AGE levels ? metformin and oligomeric procyanidin complex (OPC). Each agent has been shown to reduce AGE levels in some patients with either diabetes mellitus (metformin) or cancer (OPC). Their combination may be more effective than either agent alone. The study will be co-led by Dr. Shanora Brown from South Carolina State University (SCSU) and Dr. Michael Lilly from the Medical University of South Carolina Hollings Cancer Center (MUSC-HCC). As a Phase Ib study, the primary objective will be to define toxicity for the drug combination. However, all analyses will compare results in AA and EA participants. Aim 1 is to conduct a Phase Ib trial of a combination of metformin and OPC in PCa patients receiving androgen deprivation therapy (ADT). This aim will be led by Dr. Lilly (MUSC-HCC). Aim 2 is to perform correlative biochemical studies of inflammation and oxidative stress during the Phase Ib trial. This aim will be led by Dr. Brown (SCSU). No studies to date have investigated AGE effects on PCa treatment. The proposed study provides a novel, unifying mechanism to account for the poorer PCa response to ADT, and the higher PCa incidence, as well as poorer quality of life, in patients with obesity, oxidative stress, and hyperglycemia. This mechanistic model may also mediate cancer racial disparities in PCa outcomes.